Cardiac fibroblast GSK-3α aggravates ischemic cardiac injury by promoting fibrosis, inflammation, and impairing angiogenesis.
Angiogenesis
Fibrosis
Glycogen synthase kinase
Inflammation
Myocardial infarction
Journal
Basic research in cardiology
ISSN: 1435-1803
Titre abrégé: Basic Res Cardiol
Pays: Germany
ID NLM: 0360342
Informations de publication
Date de publication:
01 09 2023
01 09 2023
Historique:
received:
30
05
2023
accepted:
16
08
2023
revised:
14
08
2023
medline:
4
9
2023
pubmed:
1
9
2023
entrez:
1
9
2023
Statut:
epublish
Résumé
Myocardial infarction (MI) is the leading cause of death worldwide. Glycogen synthase kinase-3 (GSK-3) has been considered to be a promising therapeutic target for cardiovascular diseases. GSK-3 is a family of ubiquitously expressed serine/threonine kinases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Previously, our group identified that cardiac fibroblast (FB) GSK-3β acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of FB-GSK-3α in MI pathology is not defined. To determine the role of FB-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the residential fibroblast or myofibroblast (MyoFB) using tamoxifen (TAM) inducible Tcf21 or Periostin (Postn) promoter-driven Cre recombinase, respectively. Echocardiographic analysis revealed that FB- or MyoFB-specific GSK-3α deletion prevented the development of dilative remodeling and cardiac dysfunction. Morphometrics and histology studies confirmed improvement in capillary density and a remarkable reduction in hypertrophy and fibrosis in the KO group. We harvested the hearts at 4 weeks post-MI and analyzed signature genes of adverse remodeling. Specifically, qPCR analysis was performed to examine the gene panels of inflammation (TNFα, IL-6, IL-1β), fibrosis (COL1A1, COL3A1, COMP, Fibronectin-1, Latent TGF-β binding protein 2), and hypertrophy (ANP, BNP, MYH7). These molecular markers were essentially normalized due to FB-specific GSK-3α deletion. Further molecular studies confirmed that FB-GSK-3α could regulate NF-kB activation and expression of angiogenesis-related proteins. Our findings suggest that FB-GSK-3α plays a critical role in the pathological cardiac remodeling of ischemic hearts, therefore, it could be therapeutically targeted.
Identifiants
pubmed: 37656238
doi: 10.1007/s00395-023-01005-1
pii: 10.1007/s00395-023-01005-1
doi:
Substances chimiques
glycogen synthase kinase 3 alpha
EC 2.7.11.26
Glycogen Synthase Kinase 3
EC 2.7.11.26
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Angiogenic Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
35Subventions
Organisme : NHLBI NIH HHS
ID : R01HL133290
Pays : United States
Organisme : NHLBI NIH HHS
ID : 1R01HL143074
Pays : United States
Informations de copyright
© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Acharya A, Baek ST, Huang G, Eskiocak B, Goetsch S, Sung CY, Banfi S, Sauer MF, Olsen GS, Duffield JS, Olson EN, Tallquist MD (2012) The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 139:2139–2149. https://doi.org/10.1242/dev.079970
doi: 10.1242/dev.079970
pubmed: 22573622
pmcid: 3357908
Ahmad F, Lal H, Zhou J, Vagnozzi RJ, Yu JE, Shang X, Woodgett JR, Gao E, Force T (2014) Cardiomyocyte-specific deletion of Gsk3alpha mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J Am Coll Cardiol 64:696–706. https://doi.org/10.1016/j.jacc.2014.04.068
doi: 10.1016/j.jacc.2014.04.068
pubmed: 25125302
pmcid: 4142642
Ahmad F, Singh AP, Tomar D, Rahmani M, Zhang Q, Woodgett JR, Tilley DG, Lal H, Force T (2019) Cardiomyocyte-GSK-3alpha promotes mPTP opening and heart failure in mice with chronic pressure overload. J Mol Cell Cardiol 130:65–75. https://doi.org/10.1016/j.yjmcc.2019.03.020
doi: 10.1016/j.yjmcc.2019.03.020
pubmed: 30928428
pmcid: 6502694
Ahmad F, Woodgett JR (2020) Emerging roles of GSK-3alpha in pathophysiology: emphasis on cardio-metabolic disorders. Biochim Biophys Acta Mol Cell Res 1867:118616. https://doi.org/10.1016/j.bbamcr.2019.118616
doi: 10.1016/j.bbamcr.2019.118616
pubmed: 31785335
Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744. https://doi.org/10.1038/35036374
doi: 10.1038/35036374
pubmed: 11025665
pmcid: 2852586
Brauninger H, Kruger S, Bacmeister L, Nystrom A, Eyerich K, Westermann D, Lindner D (2023) Matrix metalloproteinases in coronary artery disease and myocardial infarction. Basic Res Cardiol 118:18. https://doi.org/10.1007/s00395-023-00987-2
doi: 10.1007/s00395-023-00987-2
pubmed: 37160529
pmcid: 10169894
Brooks HL, Lindsey ML (2018) Guidelines for authors and reviewers on antibody use in physiology studies. Am J Physiol Heart Circ Physiol 314:H724–H732. https://doi.org/10.1152/ajpheart.00512.2017
doi: 10.1152/ajpheart.00512.2017
pubmed: 29351459
pmcid: 6048465
Chalise U, Becirovic-Agic M, Lindsey ML (2023) The cardiac wound healing response to myocardial infarction. WIREs Mech Dis 15:e1584. https://doi.org/10.1002/wsbm.1584
doi: 10.1002/wsbm.1584
pubmed: 36634913
Cinetto F, Ceccato J, Caputo I, Cangiano D, Montini B, Lunardi F, Piazza M, Agostini C, Calabrese F, Semenzato G, Rattazzi M, Gurrieri C, Scarpa R, Felice C, Vianello F (2021) GSK-3 inhibition modulates metalloproteases in a model of lung inflammation and fibrosis. Front Mol Biosci 8:633054. https://doi.org/10.3389/fmolb.2021.633054
doi: 10.3389/fmolb.2021.633054
pubmed: 34235177
pmcid: 8255387
Cortes-Vieyra R, Silva-Garcia O, Gomez-Garcia A, Gutierrez-Castellanos S, Alvarez-Aguilar C, Baizabal-Aguirre VM (2021) Glycogen synthase kinase 3beta modulates the inflammatory response activated by bacteria, viruses, and parasites. Front Immunol 12:675751. https://doi.org/10.3389/fimmu.2021.675751
doi: 10.3389/fimmu.2021.675751
pubmed: 34017345
pmcid: 8129516
Doble BW, Patel S, Wood GA, Kockeritz LK, Woodgett JR (2007) Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev Cell 12:957–971. https://doi.org/10.1016/j.devcel.2007.04.001
doi: 10.1016/j.devcel.2007.04.001
pubmed: 17543867
pmcid: 4485918
Frangogiannis NG (2006) The mechanistic basis of infarct healing. Antioxid Redox Signal 8:1907–1939. https://doi.org/10.1089/ars.2006.8.1907
doi: 10.1089/ars.2006.8.1907
pubmed: 17034340
Frangogiannis NG (2015) Pathophysiology of myocardial infarction. Compr Physiol 5:1841–1875. https://doi.org/10.1002/cphy.c150006
doi: 10.1002/cphy.c150006
pubmed: 26426469
Fu X, Khalil H, Kanisicak O, Boyer JG, Vagnozzi RJ, Maliken BD, Sargent MA, Prasad V, Valiente-Alandi I, Blaxall BC, Molkentin JD (2018) Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J Clin Investig 128:2127–2143. https://doi.org/10.1172/JCI98215
doi: 10.1172/JCI98215
pubmed: 29664017
pmcid: 5957472
Gao E, Lei YH, Shang X, Huang ZM, Zuo L, Boucher M, Fan Q, Chuprun JK, Ma XL, Koch WJ (2010) A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res 107:1445–1453. https://doi.org/10.1161/CIRCRESAHA.110.223925
doi: 10.1161/CIRCRESAHA.110.223925
pubmed: 20966393
pmcid: 3005817
Ghosh S, Hayden MS (2008) New regulators of NF-kappaB in inflammation. Nat Rev Immunol 8:837–848. https://doi.org/10.1038/nri2423
doi: 10.1038/nri2423
pubmed: 18927578
Hess A, Borchert T, Ross TL, Bengel FM, Thackeray JT (2022) Characterizing the transition from immune response to tissue repair after myocardial infarction by multiparametric imaging. Basic Res Cardiol 117:14. https://doi.org/10.1007/s00395-022-00922-x
doi: 10.1007/s00395-022-00922-x
pubmed: 35275268
pmcid: 8917105
Hesse J, Owenier C, Lautwein T, Zalfen R, Weber JF, Ding Z, Alter C, Lang A, Grandoch M, Gerdes N, Fischer JW, Klau GW, Dieterich C, Kohrer K, Schrader J (2021) Single-cell transcriptomics defines heterogeneity of epicardial cells and fibroblasts within the infarcted murine heart. Elife. https://doi.org/10.7554/eLife.65921
doi: 10.7554/eLife.65921
pubmed: 34152268
pmcid: 8216715
Hoffmeister L, Diekmann M, Brand K, Huber R (2020) GSK3: a kinase balancing promotion and resolution of inflammation. Cells. https://doi.org/10.3390/cells9040820
doi: 10.3390/cells9040820
pubmed: 33158300
pmcid: 7694386
Humeres C, Frangogiannis NG (2019) Fibroblasts in the infarcted, remodeling, and failing heart. JACC Basic Transl Sci 4:449–467. https://doi.org/10.1016/j.jacbts.2019.02.006
doi: 10.1016/j.jacbts.2019.02.006
pubmed: 31312768
pmcid: 6610002
Isogai C, Laug WE, Shimada H, Declerck PJ, Stins MF, Durden DL, Erdreich-Epstein A, DeClerck YA (2001) Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res 61:5587–5594
pubmed: 11454712
Jope RS, Cheng Y, Lowell JA, Worthen RJ, Sitbon YH, Beurel E (2017) Stressed and inflamed, can GSK3 be blamed? Trends Biochem Sci 42:180–192. https://doi.org/10.1016/j.tibs.2016.10.009
doi: 10.1016/j.tibs.2016.10.009
pubmed: 27876551
Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN, Brody MJ, Lin S-CJ, Aronow BJ, Tallquist MD, Molkentin JD (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun 7:12260. https://doi.org/10.1038/ncomms12260
doi: 10.1038/ncomms12260
pubmed: 27447449
pmcid: 5512625
Kim HS, Skurk C, Thomas SR, Bialik A, Suhara T, Kureishi Y, Birnbaum M, Keaney JF Jr, Walsh K (2002) Regulation of angiogenesis by glycogen synthase kinase-3beta. J Biol Chem 277:41888–41896. https://doi.org/10.1074/jbc.M206657200
doi: 10.1074/jbc.M206657200
pubmed: 12167628
Lal H, Ahmad F, Woodgett J, Force T (2015) The GSK-3 family as therapeutic target for myocardial diseases. Circ Res 116:138–149. https://doi.org/10.1161/CIRCRESAHA.116.303613
doi: 10.1161/CIRCRESAHA.116.303613
pubmed: 25552693
pmcid: 4283216
Lal H, Ahmad F, Zhou J, Yu JE, Vagnozzi RJ, Guo Y, Yu D, Tsai EJ, Woodgett J, Gao E, Force T (2014) Cardiac fibroblast glycogen synthase kinase-3beta regulates ventricular remodeling and dysfunction in ischemic heart. Circulation 130:419–430. https://doi.org/10.1161/CIRCULATIONAHA.113.008364
doi: 10.1161/CIRCULATIONAHA.113.008364
pubmed: 24899689
pmcid: 4153405
Lal H, Zhou J, Ahmad F, Zaka R, Vagnozzi RJ, Decaul M, Woodgett J, Gao E, Force T (2012) Glycogen synthase kinase-3alpha limits ischemic injury, cardiac rupture, post-myocardial infarction remodeling and death. Circulation 125:65–75. https://doi.org/10.1161/CIRCULATIONAHA.111.050666
doi: 10.1161/CIRCULATIONAHA.111.050666
pubmed: 22086876
Lee NV, Sato M, Annis DS, Loo JA, Wu L, Mosher DF, Iruela-Arispe ML (2006) ADAMTS1 mediates the release of antiangiogenic polypeptides from TSP1 and 2. EMBO J 25:5270–5283. https://doi.org/10.1038/sj.emboj.7601400
doi: 10.1038/sj.emboj.7601400
pubmed: 17082774
pmcid: 1636613
Lendahl U, Muhl L, Betsholtz C (2022) Identification, discrimination and heterogeneity of fibroblasts. Nat Commun 13:3409. https://doi.org/10.1038/s41467-022-30633-9
doi: 10.1038/s41467-022-30633-9
pubmed: 35701396
pmcid: 9192344
Li Z, Zhu H, Liu C, Wang Y, Wang D, Liu H, Cao W, Hu Y, Lin Q, Tong C, Lu M, Sachinidis A, Li L, Peng L (2019) GSK-3beta inhibition protects the rat heart from the lipopolysaccharide-induced inflammation injury via suppressing FOXO3A activity. J Cell Mol Med 23:7796–7809. https://doi.org/10.1111/jcmm.14656
doi: 10.1111/jcmm.14656
pubmed: 31503410
pmcid: 6815822
Lindsey ML, Bolli R, Canty JM Jr, Du XJ, Frangogiannis NG, Frantz S, Gourdie RG, Holmes JW, Jones SP, Kloner RA, Lefer DJ, Liao R, Murphy E, Ping P, Przyklenk K, Recchia FA, Schwartz Longacre L, Ripplinger CM, Van Eyk JE, Heusch G (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812–H838. https://doi.org/10.1152/ajpheart.00335.2017
doi: 10.1152/ajpheart.00335.2017
pubmed: 29351451
pmcid: 5966768
Lindsey ML, Kassiri Z, Virag JAI, de Castro Bras LE, Scherrer-Crosbie M (2018) Guidelines for measuring cardiac physiology in mice. Am J Physiol Heart Circ Physiol 314:H733–H752. https://doi.org/10.1152/ajpheart.00339.2017
doi: 10.1152/ajpheart.00339.2017
pubmed: 29351456
pmcid: 5966769
Liu T, Zhang L, Joo D, Sun SC (2017) NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2:17023. https://doi.org/10.1038/sigtrans.2017.23
doi: 10.1038/sigtrans.2017.23
pubmed: 29158945
pmcid: 5661633
Lother A, Kohl P (2023) The heterocellular heart: identities, interactions, and implications for cardiology. Basic Res Cardiol 118:30. https://doi.org/10.1007/s00395-023-01000-6
doi: 10.1007/s00395-023-01000-6
pubmed: 37495826
pmcid: 10371928
Ma Y, Iyer RP, Jung M, Czubryt MP, Lindsey ML (2017) Cardiac fibroblast activation post-myocardial infarction: current knowledge gaps. Trends Pharmacol Sci 38:448–458. https://doi.org/10.1016/j.tips.2017.03.001
doi: 10.1016/j.tips.2017.03.001
pubmed: 28365093
pmcid: 5437868
Martin TA, Harding KG, Jiang WG (1999) Regulation of angiogenesis and endothelial cell motility by matrix-bound fibroblasts. Angiogenesis 3:69–76. https://doi.org/10.1023/a:1009004212357
doi: 10.1023/a:1009004212357
pubmed: 14517446
Maurer AM, Zhou B, Han ZC (2006) Roles of platelet factor 4 in hematopoiesis and angiogenesis. Growth Factors 24:242–252. https://doi.org/10.1080/08977190600988225
doi: 10.1080/08977190600988225
pubmed: 17381065
Mouton AJ, Rivera OJ, Lindsey ML (2018) Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding. Am J Physiol Heart Circ Physiol 315:H71–H79. https://doi.org/10.1152/ajpheart.00131.2018
doi: 10.1152/ajpheart.00131.2018
pubmed: 29600895
pmcid: 6087773
Nakamura M, Liu T, Husain S, Zhai P, Warren JS, Hsu CP, Matsuda T, Phiel CJ, Cox JE, Tian B, Li H, Sadoshima J (2019) Glycogen synthase kinase-3alpha promotes fatty acid uptake and lipotoxic cardiomyopathy. Cell Metab 29:1119-1134.e1112. https://doi.org/10.1016/j.cmet.2019.01.005
doi: 10.1016/j.cmet.2019.01.005
pubmed: 30745182
pmcid: 6677269
Newman AC, Nakatsu MN, Chou W, Gershon PD, Hughes CC (2011) The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Mol Biol Cell 22:3791–3800. https://doi.org/10.1091/mbc.E11-05-0393
doi: 10.1091/mbc.E11-05-0393
pubmed: 21865599
pmcid: 3192859
Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M, Pearl EJ, Petersen OH, Rawle F, Reynolds P, Rooney K, Sena ES, Silberberg SD, Steckler T, Wurbel H (2020) The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. J Physiol 598:3793–3801. https://doi.org/10.1113/JP280389
doi: 10.1113/JP280389
pubmed: 32666574
Potz BA, Sabe AA, Elmadhun NY, Clements RT, Robich MP, Sodha NR, Sellke FW (2016) Glycogen synthase kinase 3beta inhibition improves myocardial angiogenesis and perfusion in a swine model of metabolic syndrome. J Am Heart Assoc. https://doi.org/10.1161/JAHA.116.003694
doi: 10.1161/JAHA.116.003694
pubmed: 27405812
pmcid: 5015402
Saraswati S, Marrow SMW, Watch LA, Young PP (2019) Identification of a pro-angiogenic functional role for FSP1-positive fibroblast subtype in wound healing. Nat Commun 10:3027. https://doi.org/10.1038/s41467-019-10965-9
doi: 10.1038/s41467-019-10965-9
pubmed: 31289275
pmcid: 6617456
Sengupta S, Gherardi E, Sellers LA, Wood JM, Sasisekharan R, Fan TP (2003) Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 23:69–75. https://doi.org/10.1161/01.atv.0000048701.86621.d0
doi: 10.1161/01.atv.0000048701.86621.d0
pubmed: 12524227
Shams F, Moravvej H, Hosseinzadeh S, Mostafavi E, Bayat H, Kazemi B, Bandehpour M, Rostami E, Rahimpour A, Moosavian H (2022) Overexpression of VEGF in dermal fibroblast cells accelerates the angiogenesis and wound healing function: in vitro and in vivo studies. Sci Rep 12:18529. https://doi.org/10.1038/s41598-022-23304-8
doi: 10.1038/s41598-022-23304-8
pubmed: 36323953
pmcid: 9630276
Shinde AV, Frangogiannis NG (2014) Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol 70:74–82. https://doi.org/10.1016/j.yjmcc.2013.11.015
doi: 10.1016/j.yjmcc.2013.11.015
pubmed: 24321195
Skurk C, Maatz H, Rocnik E, Bialik A, Force T, Walsh K (2005) Glycogen-Synthase Kinase3beta/beta-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells. Circ Res 96:308–318. https://doi.org/10.1161/01.RES.0000156273.30274.f7
doi: 10.1161/01.RES.0000156273.30274.f7
pubmed: 15662032
Tallquist MD, Molkentin JD (2017) Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol 14:484–491. https://doi.org/10.1038/nrcardio.2017.57
doi: 10.1038/nrcardio.2017.57
pubmed: 28436487
pmcid: 6329009
Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Beaton AZ, Boehme AK, Buxton AE, Commodore-Mensah Y, Elkind MSV, Evenson KR, Eze-Nliam C, Fugar S, Generoso G, Heard DG, Hiremath S, Ho JE, Kalani R, Kazi DS, Ko D, Levine DA, Liu J, Ma J, Magnani JW, Michos ED, Mussolino ME, Navaneethan SD, Parikh NI, Poudel R, Rezk-Hanna M, Roth GA, Shah NS, St-Onge MP, Thacker EL, Virani SS, Voeks JH, Wang NY, Wong ND, Wong SS, Yaffe K, Martin SS, American Heart Association Council on E, Prevention Statistics C, Stroke Statistics S (2023) Heart disease and stroke statistics—2023 update: a report from the American Heart Association. Circulation 147:e93–e621. https://doi.org/10.1161/CIR.0000000000001123
doi: 10.1161/CIR.0000000000001123
pubmed: 36695182
Umbarkar P, Ejantkar S, Tousif S, Lal H (2021) Mechanisms of fibroblast activation and myocardial fibrosis: lessons learned from FB-specific conditional mouse models. Cells. https://doi.org/10.3390/cells10092412
doi: 10.3390/cells10092412
pubmed: 34572061
pmcid: 8471002
Umbarkar P, Ruiz Ramirez SY, Toro Cora A, Tousif S, Lal H (2023) GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit. Biochim Biophys Acta Mol Basis Dis 1869:166724. https://doi.org/10.1016/j.bbadis.2023.166724
doi: 10.1016/j.bbadis.2023.166724
pubmed: 37094727
Umbarkar P, Singh AP, Gupte M, Verma VK, Galindo CL, Guo Y, Zhang Q, McNamara JW, Force T, Lal H (2019) Cardiomyocyte SMAD4-dependent TGF-beta signaling is essential to maintain adult heart homeostasis. JACC Basic Transl Sci 4:41–53. https://doi.org/10.1016/j.jacbts.2018.10.003
doi: 10.1016/j.jacbts.2018.10.003
pubmed: 30847418
pmcid: 6390466
Umbarkar P, Tousif S, Singh AP, Anderson JC, Zhang Q, Tallquist MD, Woodgett J, Lal H (2022) Fibroblast GSK-3alpha promotes fibrosis via RAF-MEK-ERK pathway in the injured heart. Circ Res 131:620–636. https://doi.org/10.1161/CIRCRESAHA.122.321431
doi: 10.1161/CIRCRESAHA.122.321431
pubmed: 36052698
Vidal R, Wagner JUG, Braeuning C, Fischer C, Patrick R, Tombor L, Muhly-Reinholz M, John D, Kliem M, Conrad T, Guimaraes-Camboa N, Harvey R, Dimmeler S, Sauer S (2019) Transcriptional heterogeneity of fibroblasts is a hallmark of the aging heart. JCI Insight. https://doi.org/10.1172/jci.insight.131092
doi: 10.1172/jci.insight.131092
pubmed: 31723062
pmcid: 6948853
Wang CQ, Huang YW, Wang SW, Huang YL, Tsai CH, Zhao YM, Huang BF, Xu GH, Fong YC, Tang CH (2017) Amphiregulin enhances VEGF-A production in human chondrosarcoma cells and promotes angiogenesis by inhibiting miR-206 via FAK/c-Src/PKCdelta pathway. Cancer Lett 385:261–270. https://doi.org/10.1016/j.canlet.2016.10.010
doi: 10.1016/j.canlet.2016.10.010
pubmed: 27826039
Wang L, Wang Y, Zhang C, Li J, Meng Y, Dou M, Noguchi CT, Di L (2018) Inhibiting glycogen synthase kinase 3 reverses obesity-induced white adipose tissue inflammation by regulating apoptosis inhibitor of macrophage/CD5L-mediated macrophage migration. Arterioscler Thromb Vasc Biol 38:2103–2116. https://doi.org/10.1161/ATVBAHA.118.311363
doi: 10.1161/ATVBAHA.118.311363
pubmed: 30026270
Wang L, Yang Y, Ma H, Xie Y, Xu J, Near D, Wang H, Garbutt T, Li Y, Liu J, Qian L (2022) Single-cell dual-omics reveals the transcriptomic and epigenomic diversity of cardiac non-myocytes. Cardiovasc Res 118:1548–1563. https://doi.org/10.1093/cvr/cvab134
doi: 10.1093/cvr/cvab134
pubmed: 33839759
Zhou J, Freeman TA, Ahmad F, Shang X, Mangano E, Gao E, Farber J, Wang Y, Ma XL, Woodgett J, Vagnozzi RJ, Lal H, Force T (2013) GSK-3alpha is a central regulator of age-related pathologies in mice. J Clin Investig 123:1821–1832. https://doi.org/10.1172/JCI64398
doi: 10.1172/JCI64398
pubmed: 23549082
pmcid: 3613907
Zhou J, Lal H, Chen X, Shang X, Song J, Li Y, Kerkela R, Doble BW, MacAulay K, DeCaul M, Koch WJ, Farber J, Woodgett J, Gao E, Force T (2010) GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice. J Clin Investig 120:2280–2291. https://doi.org/10.1172/JCI41407
doi: 10.1172/JCI41407
pubmed: 20516643
pmcid: 2898595